1. Field of the Invention
The present invention relates generally to articles which are designed to be in contact with biologically active agents. Such articles include implant devices and other structures which are designed to be utilized in vivo. Such articles also include containers, supports, and transport systems wherein biologically active agents are in continual contact with the surfaces of, the article. More particularly, the present invention relates to reducing and thereby controlling the degree to which biologically active agents bind to the surfaces of such articles.
2. Description of Related Art
Most biologically active agents interact with other molecules present on either surfaces or membranes. In fact, the effectiveness of many biological systems is dependent on the presence of certain intrinsic binding properties between biologically active agents and biological surfaces. For example, biological surfaces, such as endothelial linings or receptor-embedded cell membranes, incorporate high affinity (energy) binding properties to achieve optimal biological function. Although the binding properties of biologically active agents is essential for proper biological function, there are many situations where binding of these biologically active agents to non-biological surfaces presents a problem. For example, the coagulation protein factor XII is a biologically active agent which binds to healthy vascular endothelial cells. Protein factor XII plays an important role in the naturally occurring coagulation process. However, when protein factor XII binds to the surface of an implanted biomaterial, the result may be a thrombotic or thromboembolic complication of the prosthetic device.
Other situations where reduced surface binding of biologically active agents would be desirable include vessels used to transport biologically active agents. In these situations, binding of the agent to the wall of the transport container results in reduced yield of the transported product. In addition, reduced binding would be desirable in a vascular prosthesis where interactions of biologically active agents can promote complications and reduce the medical utility of the device. For example, it would be desirable to reduce surface binding of biologically active agents to hip prostheses where the binding of such agents can result in denaturization of the agents and the initiation of an inflammatory reaction clinically associated with pain and reduced utility of the device.
Another situation where reduced and thereby controlled surface binding of biologically active agents would be desirable includes the fabrication of biological opto-electronic devices. These devices would provide electronic output from electron transporting biologically active molecules responding to photoelectric, thermal, or other environmental stimulus. To fabricate these devices, only limited numbers of biologically active molecules would be deposited ideally on a solid support. Moreover, the reduced and thereby controlled binding of the biologically active molecules would ideally not result in conformational denaturation of the molecules.
The non-biological materials which are commonly used in the manufacture of biomedical and food service devices include polymers, ceramics and metals, most of which have high surface energies. These high surface energies result frequently in increased binding of biologically active molecules in situations, such as those described above, where such binding is undesirable. Accordingly, it would be desirable to provide a treatment for the surfaces of such non-biological materials which would effectively reduce the surface energy and thereby decrease undesirable binding of biologically active agents thereto.
Over the years, various materials have been developed for use as surface modifying agents which reduce the binding of biologically active agents to their surfaces. Examples include polymers, such as silicone, polystyrene, polyethylene and polytetrafluoroethylene. All of these materials have low surface energies. Accordingly, the binding affinities between these materials and biologically active agents is reduced. These materials are generally used in bulk form, i.e., the entire device is made from the materials.
More recently, different alcohol based compounds have been either physically adsorbed or chemically bonded to the surface of non-biological materials to reduce the subsequent surface binding of biologically active agents. Among the more commonly used are polyethylene glycol and sodium heparin. While affording improved resistance to absorption of proteins and other biologically active agents, these two exemplary materials are each subject to their own specific problems. For example, non-biological surfaces, such as immunoaffinity chromatography columns and electrophoretic capillaries, have been coated with polyethylene glycol. Although such coatings have reduced binding of biologically active agents, the nephrotoxic effects of polyethylene glycol are well documented. Further, binding of polyethylene glycol to the non-biological surface is possible only through various forms of covalent chemistry.
Sodium heparin is a well-recognized anti-coagulation factor whose use entails correlative physiological effects. Most often, sodium heparin is covalently bound directly to the non-biological surface or indirectly through various carbon chain extenders. In addition, sodium heparin has been physically absorbed onto the non-biological surface. Other surface modification techniques have involved the coating of electrophoretic capillaries with phosphate moieties and conventional silanes and polyacrylimides.
Other attempts at reducing the surface activity of non-biological materials have involved the covalent bonding of maltose to silica substrates wherein an additional silicone-based intermediate moiety (3-aminopropyltriethoxysilane) is covalently bound to both the fused-silica capillary walls and the disaccharide. In another procedure, cellulose has been absorbed onto non-biological surfaces. Specifically, methylcellulose has been used to coat the inside of quartz electrophoresis tubes to reduce or eliminate electroendosmosis. The protocol used in applying the methylcellulose coating involves three steps. First, the electrophoresis tube is washed with detergent. The possibility of detergent residues present on the quartz surface is not desirable since it may block carbohydrate adsorption. The second step involves addition of formaldehyde and formic acid to the methylcellulose solution to catalyze the cross-linking of the carbohydrate molecules which are present in the coating. Finally, the quartz tube is heated between applications of the methylcellulose.
There presently is a need to provide a simple, quick, and efficient technique for reducing the surface energy of articles which are designed for use in contact with biologically active agents. The technique should be capable of reducing surface energy levels sufficiently to reduce and thereby control the binding of biologically active agents to the article's surface.